Keto substituted alkylidenedithiobisphenols

ABSTRACT

COMPOUNDS HAVING THE GENERAL FORMULA:   3,5-DI(T-C4H9-),4-(HO-),1-((3,5-DI(T-C4H9-),4-(HO-)PHENYL)   -S-C(-CH3)(-R)-S-)BENZENE   WHERE R IS AN ALKYL RADICAL SUBSTITUTED BY A RADICAL SELECTED FROM THE CLASS CONSISTING OF ALKOXY, CARBONYL AND ESTER RADICALS. THE COMPOUNDS ARE USEFUL FOR REDUCING BLOOD CHOLESTEROL IN WARM-BLOODED ANIMALS.

United States Patent 3,786,100 KETO SUBSTITUTED ALKYLIDENEDITHIO-BISPHENOLS Martin B. Neuworth, Trumbull, Conn., assignor to ContinentalOil Company, Ponca City, Okla. 5

No Drawing. Original application June 23, 1969, Ser. No.

835,811, now abandoned. Divided and this application Dec. 10, 1971, Ser.No. 206,929

Int. Cl. C07c 149/32 where R is an alkyl radical substituted by aradical selected from the class consisting of alkoxy, carbonyl and esterradicals. The compounds are useful for reducing blood cholesterol inwarm-blooded animals.

CROSS-REFERENCE TO RELATED APPLICATION This is a division ofapplication, Ser. No. 835,811, filed June 23, 1969, now abandoned, whichwas itself a continuation-in-part of patent applications, Ser. Nos.637,622; 637,649; and 637,650, all filed May 11, 1967, and all nowabandoned.

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to a new and useful group of sulfur-containing bisphenols.

Description of the prior art US. Pats. Nos. 2,278,224 and 2,472,318describe compounds defined by the formula DRxR'xRD, in which R is arylor alkyl aryl, or a substituted aryl or alkyl aryl group, x is a sulfur,oxygen or tellurium, but preferably a sulfur group, R is an alkyl orsubstituted alkyl group and D is an inhibitor group taken from the classof hydroxy, amino, sulfide, disulfide, or polysulfide groups.

SUMMARY OF THE INVENTION The novel chemical compounds of the presentinvention possess the property of lowering the cholesterol content ofthe blood of warm-blooded animals. They have the following generalformula:

HO OH where R is an alkyl radical substituted by a radical selected fromthe class consisting of alkoxy, carbonyl and ester radicals.

The compounds of the present invention are prepared as follows. Theappropriate 4-mercaptophenol is reacted with the appropriate carbonylcompound in the presence 3,786,100 Patented Jan. 15, 1974 of a strongacid catalyst according to the following equation:

where R is an alkyl radical substituted by a radical selected from theclass consisting of alkoxy, carbonyl and ester radicals. The appropriate4-mercaptophenol may be prepared by any one of several known methods.For example, thiocyanation of the appropriate phenol, followed byreduction, is one of such methods. For details, see Organic Reactions,vol. IH, chapter 6, by Roger Adams et al.; also the article by Muller etal., entitled Untersuchungen an schwefelhaltigen Aroylen mittels derElectronenresonanz in Liebigs Annalen (1961, Ed. 645, p. 79); and,finally, U.S. Pat. 3,129,262.

The mercaptophenol and the appropriate carbonyl compound are preferablydissolved in an inert organic solvent to provide a homogeneous reactionmixture. At least a stoichiometric amount of the carbonyl compound isused. The catalyst is a strong acid catalyst, for example hydrochloricacid, sulfuric acid, perchloric acid, and strong acid cationic exchangeresins. The reaction is mildly exothermic initially; external heating isthen re-- quired to maintain the reaction temperature, generally between50 and 100 C. Reaction times of 0.8 to 6 hours are generally required.

The following examples illustrate the compounds of this invention. Ineach example, the chemical name and structural formula of the compoundare first given. The identity of the compound produced in each examplewas established by conventional methods of analysis.

EXAMPLE .1

Preparation of 2,4 pentanedione ::2,2-bis 3,5 -di-t-butyl-4-hydroxyphenyl) mercaptal A SOD-milliliter flask (stirrer, thermometer,condenser) was charged with 23.8 grams of2,6-di-t-butyl-4-mercaptophenol (0.1 mole) and 5.0 grams of2,4-pentanedi0ne (0.05 mole) in 150 milliliters of methanol. 8.6Milliliters of 12 N HCl was added, and the mixture held at about 70 C.for about three hours. The product mixture was placed in a separatoryfunnel to which 100 milliliters of hexane and 200 milliliters of H 0were added. The aqueous phase was drained. A solid product was recoveredfrom the hexane solution by partial stripping of the solvent. The solidwas recrystallized from ethanol (USP). It weighed 15.6 grams and had amelting point of 126-130 C.

3 EXAMPLE 2 Preparation of 2,4-pentanedione: 2,2-bis(3,5-di-t-butyl-4-hydroxyphenyl)mercaptal, 4,4-diethylacetal A 500-milliliter flask(stirrer, thermometer, condenser with H O scrubber, gas inlet) wascharged with 47.6 grams of 2,6-di-t-butyl-4-mercaptophenol (0.2 mole)and 5.0 grams of pentanedione (0.05 mole) in 166 milliliters ofanhydrous ethyl ether. The solution was saturated with dry gaseous HCl,and maintained at about 80 C. for about 30 minutes. The product wasplaced in a flask and stripped of most of the solvent under H O pumpvacuum with moderate heating. A heavy oil precipitated. 70 millilitersof benzene Was added to the flask and the resultant solution was placedin a separatory funnel and washed with 100 milliliters of H 0. Theorganic phase was then washed with two 100-milliliter portions of 5%caustic solution. The caustic fraction was drained oif. The benzenephase was stripped of benzene by a water aspirator vacuum. A viscous oilformed which was dissolved in 40 milliliters of hexane and then cooledin a Dry Ice chest. A crystalline product was obtained which wasfiltered on chilled equipment; washed with very cold hexane; and driedin a vacuum desiccator. It weighed 8.8 grams and had a melting point of96105 C. This was recrystallized from 20 milliliters of ethanol;filtered; washed with ethanol; and dried in a vacuum desiccator (38 0.).Its weight was 5.2 grams and its melting point was 120- 122.5 C.

EXAMPLE 3 Preparation of 2-octanone: bis(3,5-di-t-butyl-4- hydroxyphenylmercaptal A 500-milliliter flask (stirrer, thermometer, condenser with HO scrubber, gas inlet) was charged with 23.8 grams of2,6-di-t-butyl-4-mercaptophenol (0.1 mole) and 6.4 grams of 2-octanone(0.05 mole) (the stoichiometric amount was used rather than the usual100% excess because of the difliculty of removing the unused ketone fromthe reaction mixture), in 150 milliliters of methanol. The charge washeated to about 50 C., saturated with gaseous HCl, and held at 68 C. forabout six hours. A crystalline precipitate formed. The product mixturewas filtered, washed with 100 milliliters 90% MeOH and air dried. Itweighed 27.3 grams and had a melting point of 126-l27 C. The yield was90%.

EXAMPLE 4 Preparation of acetoacetic acid: 3 thio, ethyl ester;bis-(3,5-di-t-butyl-4-hydroxyphenyl)mercaptal A 500-milliliter flask(stirrer, thermometer, condenser, sparge tube, heating mantle) wascharged with 47.6 grams of 3,5-di-t-butyl-4hydroxythiophenol, 13.0 gramsof ethyl acetoacetate, and 150 milliliters of anhydrous ethanol. Themixture was saturated with HCI gas. In 3 minutes the temperature rosefrom 19 to 74 C.; was held at reflux 2 hours; cooled; and diluted with50 milliliters water to precipitate a heavy white paste. The paste wastaken up in 100 milliliters benzene and 100 milliliters chloroform;washed to neutrality with three 100-milliliter portions of water; anddried over MgSO The mixture was filtered and the benzene distilled offto yield a yellow viscous oil which crystallized upon standing. 25.4grams of product were recovered having a melting point of 104 to 108 C.The yield was 43 percent.

EXAMPLE 5 Preparation of 2-pentanone: 4-methyl,bis(3,5-di-tbutyl-4-hydroxyphenyl mercaptal t-C 4110 t- C 11 CH: H O S SO H CH3 t- 4110 A t- 4H0 CHa- I H CH A SOD-milliliter flask (stirrer,thermometer, condenser with H O scrubber, gas inlet) was charged with23.8 grams of 2,6-di-t-butyl-4-mercaptophenol (0.1 mole) and 10.0 gramsof methyl isobutyl ketone (0.1 mole) in 150 milliliters methanol. Thesolution was heated to about 50 C. and saturated with HCl. The mixturewas held at a temperature near 70 C. for about six hours. A crystallinesolid had formed in the flask. The mixture was filtered; washed with 100milliliters of methanol; and dried. 12.8 grams of product were recoveredhaving a melting point of 126 130 C. The yield was 44 percent.

EXAMPLE 6 Preparation of pyruvic acid: 2-thio, ethyl ester, bis(3,5-di-t-butyl-4-hydroxyphenyl)mercaptal A 500-milliliter flask (stirrer,thermometer, sparge tube, condenser, heating mantle) was charged with47.6 grams of 2,6-di-t-butyl-4-mercaptophenol, 11.6 grams of ethylpyruvate, and 150 milliliters of anhydrous denatured ethanol. Themixture was warmed to 35 C. to aid in dissolving the large chunks ofmercaptophenol. Then, HCl gas was introduced (in 3 minutes, thetemperature rose from 35 C. to 66 C.), and the solution was refluxed for2 hours. The mixture was diluted with 200 milliliters of water andextracted with 100, then 50, milliliters of benzene. The combinedbenzene phases were washed to neutrality with three -milliliter portionsof water, and dried over MgSO The mixture was filtered and stripped ofbenzene to yield a yellow solid precipitate. 33.9 grams of white solidwere recovered which had a melting point of 117 to 118 C.

The compounds of the present invention are useful for reducing the levelof cholesterol in the blood of warmblooded animals. They may be employeddirectly in suitable dosage, or as the active ingredient in a feedcomposition, or with suitable nontoxic carriers. Good results areobtained with dosages of from 15 to 600 milligrams of active compoundper kilogram of body weight of the recipient to provide a total intakeof up to 3000 mg./kg. per 24 hours.

The following table tabulates the percent reduction of cholesterol inthe blood of rodents eflected by the use of compounds of this invention.The compound was added to commercial rodent chow at a level of 0.125% byweight, and the mice were allowed to feed ad libitum for two weeks. Atthe end of this period, serum cholesterol determinations were performedon all the mice.

TABLE I Percent cholesterol reduction Compound: Percent reductionExample 1 2,4-pentanedione: 2,2-bis-(3,5-di-t-butyl 4hydroxyphenyhmercaptal 46 Example 2 2,4-pentanedione:2,2-bis-(3,5-di-tbutyl 4 hydroxyphenyl)mercaptal-4,4-diethyl acetal 58Example 3 2-octanone: Bis-(3,5-di-t-butyl 4 hydroxyphenyl)mercaptal 17Example 4 Acetoacetic acid: 3-thio, ethyl ester,bis-(3,5-dit-butyl-4-hydroxyphenyl)mercaptal 51 Example 5 2-pentanone:4-methyl-bis-(3,5 di t-butyl-4-hydroxyphenyl)mercaptal 21 Example 6Pyruvic acid: 2-thio, ethyl ester,bis-(3,5-di-tbutyl-4-hydroxyphenyl)mercaptal 24 The percent reductionsin cholesterol content set forth in the foregoing Table I werecalculated from statistically significant data. The general procedurewas as follows:

Separate portions of balanced rodent mash were mixed together with eachtest compound to prepare a series of separate compositions eachcontaining 0.125 percent by weight of one test compound. Separate groupsof male mice of the same origin and past history were fed for two weekson separate diets consisting of one of the abovedescribed compositions.Based on observations of average consumption of the composition and theconcentration of the test compound, each mouse received an estimatedoral dosage of about 250 milligrams of test compound per kilogram ofanimal body weight per day. A separate group of similar male mice wasfed for two weeks on a diet consisting of an identical rodent mash whichcontained no test compound to serve as a check. At the end of thetwo-week period, the mice in each group were anesthetized with ether andexsanguinated.

Serum cholesterol levels were determined for each mouse by taking a 0.05milliliter aliquot of serum from each mouse and adding to the aliquot 3milliliters of a 0.08 percent solution of ferric chloride in pure aceticacid. The serum was mixed with the ferric chloride-acetic acid solutionand the mixture was allowed to stand for 10 to 15 minutes to flocculateprotein. The protein was precipitated by centrifugation and the clearsupernatent fluid was transferred to a stoppered test tube. Twomilliliters of sulfuric acid was added to the supernatant and mixedwell. The tubes were then left to stand exposed to air for 20 to 30minutes. Serum cholesterol was determined by measuring the percenttransmission at a wave length of 560 millimicrons in a spectrophotometerand comparing the percent transmisison to that observed with solutionscontaining known amounts of cholesterol.

The average serum cholesterol level in milligrams of cholesterol permilliliters of serum was calculated for each test group and for thecheck group. The percentage reduction in serum cholesterol level wascalculated by dividing the dilference between the cholesterol levels inthe test group and the check group by the cholesterol level in the checkgroup and multiplying the quotient by 100.

According to the provisions of the patent statutes, I have explained theprinciple, preferred construction, and mode of operation of my inventionand have illustrated and described what I now consider to represent itsbest embodiment. However, I desire to have it understood that, withinthe scope of the appended claim, the invention may be practicedotherwise than as specifically illustrated and described.

I claim:

1. 2,4 pentanedione:2,2-bis-(3,5-di-t-butyl-4-hydroxyphenyl)-mercaptal.

References Cited UNITED STATES PATENTS 3,310,587 3/1967 OShea 260609 F3,485,843 12/1969 Wang 260609 F 3,489,804 1/1970 OShea 260609 F3,576,883 4/1971 Neuworth 260609 F LEWIS GOTTS, Primary Examiner D. R.PHILLIPS, Assistant Examiner US. Cl. X.R.

